Aetiology of Legg-Calvé-Perthes disease: A systematic review

Table 3 Main findings of the included animal studies

Ref.	Subjects	Association/molecule studied	Results
Suehiro et al[49] (2005)	Mouse model	Osteonecrosis in rat model	Repetitive mechanical stress on the femoral heads from 5 wk to 9 wk of age played an important role in the aetiology of osteonecrosis
Gershuni et al[59] (1983)	Hip of the immature pig	Joint tamponade in LCPD animal model	The data from this experiment do not support the theory that tamponade of the femoral capital epiphysis is the cause of osteonecrosis in Legg-Calvé-Perthes syndrome
Cheon et al[66] (2015)	10 piglets	Quantitative MRI in piglet model of LCPD	The epiphyseal ADC values of the ischemic hip decreased immediately (1 hour) after embolization. However, they increased rapidly at 1 wk after embolization and remained elevated until 4 wk after embolization. Perfusion MRI of ischemic hips showed decreased epiphyseal perfusion with decreased Kep immediately after embolization.
Li et al[67] (2006)	20 femoral heads of 10 piglets	MRI in piglet model of LCPD	Gadolinium-enhanced MRI can identify early ischemia and its reversal of the capital femoral epiphysis induced by hip hyper-abduction
Babyn et al[68] (1998)	Piglet model	MRI in piglet model of LCPD	High resolution MRI can demonstrate changes in the CE associated with ischemic injury and may have a role in the assessment of the CE and its development after ischemic injury.
Li et al[69] (2008)	25 piglets models	Diffusive MRI in a model of LCPD	Histological study revealed necrosis of chondrocytes and osteocytes and abnormal thickening of the epiphyseal cartilage in the ischemic femoral head.
Levin et al[70] (1999)	Rat model	Epiphysis studies in a rat model	Thickening and condensation of the subchondral bone, leading to increased stiffness of the subchondral zone, result in the osteoarthritis-like disorder. Mimicking the well-known phases of human osteonecrosis, the model readily allows for preclinical studies of therapeutic regimens.
Kandzierski et al[71] (2004)	Calf femurs	Calf femur experimental study	The author concludes that impaired blood flow within the growth layers additionally weakens the immature bone tissue of the femoral head and neck, which may lead to mechanical damage of the bone tissue itself, as well as to the epiphyseal blood vessels entering bony epiphysis.
Suehiro et al[72] (2000)	Twenty femora from 10 Wistar Kyoto rats	Standing and induction of OA	Repetitive mechanical stress on the femoral heads from 5 wk to 9 wk of age played an important role in the aetiology of osteonecrosis
Naito et al[74] (1992)	Canine femoral head	Acute effect of traction, compression, and hip joint tamponade on blood flow of the femoral head	These experimental data may have important implications for the pathogenesis of iatrogenic avascular necrosis in the treatment of congenitally dislocated hip, Legg-Perthes disease and avascular necrosis following nondisplaced femoral neck fracture
Kim et al[77] (2013)	56 immature pigs	MRI in the initial stage of LCPD	Acute ischemic injury to the immature femoral head induced severe hypoxia and cell death in the bony epiphysis and the deep layer of the epiphyseal cartilage. Viable chondrocytes in the superficial layer of the epiphyseal cartilage showed HIF-1α activation and VEGF upregulation with subsequent revascularization occurring in the cartilage.
Zhang et al[81] (2015)	6-wk-old Sprague Dawley rats	HIF-1α and LCPD	Hypoxia might be an etiological factor for femoral head necrosis. HIF-1α, VEGF as well as apoptotic genes participated in the pathophysiological process of ischemic osteonecrosis.
Kim et al[83] (2009)	56 immature pigs	HIF-1α and LCPD	Acute ischemic injury to the immature femoral head induced severe hypoxia and cell death in the bony epiphysis and the deep layer of the epiphyseal cartilage. Viable chondrocytes in the superficial layer of the epiphyseal cartilage showed HIF-1α activation and VEGF upregulation with subsequent revascularization occurring in the cartilage.

LCPD: Legg-Calvé-Perthes disease; HIF-1: Hypoxia-inducible factor; VEGF: Vascular endothelial growth factor; MRI: Magnetic resonance imaging.